Sublingual administration of riluzole

ABSTRACT

Disclosed is sublingual administration of riluzole. In particular, a method for treating a neuropsychiatric disorder or symptom by administering a sublingual formulation of riluzole is provided. In addition, a method of relieving or reducing oral pain using the sublingual formulation of riluzole is disclosed.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. ProvisionalApplication Ser. No. 62/083,068, filed Nov. 21, 2014, the disclosure ofwhich is incorporated herein in its entirety.

TECHNICAL FIELD

The present invention relates to sublingual administration of riluzoleand methods using a sublingual formulation of riluzole.

BACKGROUND

Riluzole (6-(trifluoromethoxy)benzothiazol-2-amine) is a pharmaceuticalwhich has been used for treatment of amyotrophic lateral sclerosis(ALS). Recently, riluzole has been shown to have other clinicalbenefits. For example, orally administered riluzole dosed twice a day ata total dose of 100 mg may relieve or treat neuropsychiatric symptomsand disorders, such as mood, anxiety disorder, refractory depression,obsessive-compulsive anxiety and the like.

However, such therapeutic neuropsychiatric effects via current oraldosing are not evident until multiple days after administration, or upto weeks, and at doses of 100 mg/day. The current oral administration iscurrently limited by poor solubility, variable absorption, undesirabletolerability including increased liver function abnormalities andextensive first past metabolism requiring high doses. Despite beingapproved for ALS, extensively researched in neuropsychiatric disordersand commercially available for over 20 years, the clinically undesirableeffects of riluzole have not been overcome and have limited its use. Theintrinsic property of the drug itself teaches away from the sublingualadministration of riluzole. Riluzole has a very low solubility in water,poor oral palatability, pH dependent chemical stability, and intense aswell as persistent numbness or burning sensation throughout the oralcavity. Techniques aimed at reducing these undesirable effects, such asuse of chelating agents, would only facilitate the oral swallowing andgastric absorption rather than resulting in sublingual absorption. Noveladministration of riluzole and effects thereof have not been addressedfor improving therapeutic use, particularly in neuropsychiatrictreatment, or to attenuate undesirable adverse effects. Further teachingaway from the use of sublingual riluzole, sublingual routes ofadministration with medications approved to date have been limited todelivering doses from the microgram range up to 10 mg. There are noexamples in the art of sublingual medications dosed significantly above10 mg. There has also been no sublingual formulation or use of riluzoledespite its availability for over 20 years.

As such, an alternative route for administrating riluzole for extendedtherapeutic and clinical use is desired.

SUMMARY OF THE INVENTION

The present invention provides: 1) a novel method of sublingualadministration of riluzole to a subject, particularly to a human, inneed thereof, 2) unexpected low doses of riluzole that possesstherapeutic effects across disease indications including desirableneuropsychiatric effects, and 3) the ability to provide a larger thanexpect dose of riluzole in a sublingual formulation.

The sublingual formulation as provided in the present inventioncomprises an effective amount of riluzole or a pharmaceuticallyacceptable salts, solvate, anomers, enantiomers, hydrate or prodrugsthereof. The formulation provides sufficient solubility for riluzole tobe incorporated into the sublingual formulation at relatively largedoses and sublingually delivered. The formulation is preferably amodified oral disintegrating formulation of riluzole.

In another aspect, a method of treating a disease of a subject byadministering a sublingual formulation is provided. The method comprisesproviding a sublingual formulation made using the process describedherein having an effective amount of riluzole or a pharmaceuticallyacceptable salts, solvate, anomers, enantiomers, hydrate or prodrugsthereof, and administering the formulation to a subject to treat thedisease state. The riluzole is preferably delivered in a once per dayformat but if needed, two or more doses per day may be used.

The subject may be a human.

The disease may be a neuropsychiatric disorder or symptom. Inparticular, the neuropsychiatric disorder may be anxiety disorders,generalized anxiety disorder, panic disorder, social anxiety, mooddisorders, cognitive disorders, schizophrenia, dementia, agitation,apathy, anxiety, psychoses, post-traumatic stress disorders,irritability, disinhibition, learning disorders, memory loss,personality disorders, bipolar disorders, obsessive-compulsivedisorders, autism, Rett syndrome, eating disorders, conduct disorders inDSM-5 and or combinations thereof. The disease state may also includeneurodegenerative disorders, pain disorders, ALS, cerebellar ataxia,other ataxia. Huntington's disease, Parkinson's disease, supranuclearpalsy, frontotemporal dementia, frontotemporal lobar degeneration,delirium, Alzheimer's disease, mild cognitive impairment, mild cognitiveimpairment due to Alzheimer's disease, drug addiction, tinnitus, andmental retardation.

In addition, the neuropsychiatric symptom may be anxiety, depression,stress, fatigue, feelings of panic, fear, uneasiness, problems insleeping, cold or sweaty hands and/or feet, mood liability, mania,impaired concentration or attention, cognitive problems, obsessions,compulsions, repetitive behaviors, aggression, social phobias orimpairments, stage fright, shortness of breath, heart palpitations, aninability to be still and calm, dry mouth, numbness or tingling in thehands or feet, nausea, muscle tension, dizziness apathy, elation,disinhibition, irritability, wandering, irritable bowel, belly pain,belly discomfort, diarrhea, change in bowel habits, abdominal bloating,abdominal gas, abdominal bloating, constipation or combinations thereof.

The effective amount of riluzole for the sublingual formulation of thepresent invention to achieve a lower therapeutic dose may be less thanthat of orally administered riluzole. Moreover, effective dose of thesublingual formulation of the riluzole may be about 1 to 95% of that ofthe orally administered riluzole.

The sublingual formulation of riluzole may produce a rapid therapeuticonset of action within minutes or an onset that is quicker than theorally swallowed dose. Further, the sublingual formulation of riluzoleis associated with minimal or no oral numbness. The palatability is alsogood while still resulting in sublingual absorption.

According to the present invention, the method of treating the diseaseof the subject by administering the sublingual formulation may reduceside effects of riluzole including attenuates liver functionabnormalities, which is associated with the orally administeredriluzole. According to the present invention, the method of treating thedisease of the subject by administering the sublingual formulation mayreduce the total drug load necessary to result in a therapeutic effect.A lower sublingual dose of the formulation may deliver similar effectscompared to a higher oral dose or even enhanced effects compared to ahigher oral dose.

The sublingual formulation for treating neuropsychiatric disorders orsymptoms may be dosed at or below about 200 mg/day, at or below about100 mg/day, at or below about 70 mg/day, at or below about 60 mg/day, ator below about 50 mg/day, at or below about 42.5 mg/day, at or belowabout 37.5 mg/day at or below about 35 mg/day, at or below about 20mg/day, at or below about 17.5 mg/day, at or below about 15 mg/day, ator below about 10 mg/day, at or below about 5 mg/day, or at or belowabout 1 mg/day.

According to the method of the present invention, a therapeutic effectmay begin within about 30 min after administration, within about 20 minafter administration, within about 15 min after administration, withinabout 10 min after administration, within about 5 min afteradministration, within about 4 min after administration, within about 3min after administration, within about 2 min after administration, orwithin about 1 min after administration.

The method of treating a disease of a subject by administering asublingual formulation may further comprise using the sublingualformulation including a riluzole prodrug, which may help to minimizeparethesias or numbness associated with the riluzole.

Riluzole may also be formulated into a intranasal delivery system. Whilethis could be in the form of a “wet” spray, preferably the riluzole isdissolved in a solution and the solution is freeze dried and pulverizedor milled, if necessary, to form a powder-like formulation. Thispowder-like formulation can be loaded into multi-use inhalers orpackaged into individual packets for use in single dose inhalers. Theintranasal delivery system may also make use of riluzole dissolved insolution or in suspension, loaded into an inhaler and packaged forindividual or multiple uses. Both the sublingual formulation and theintranasal spray bypass the gut, allowing a different absorption profilethan an oral tablet.

In still another aspect, a method of relieving or reducing oral pain ofa subject is provided. The method may comprise administering aneffective amount of riluzole or a pharmaceutically acceptable salts,solvate, anomers, hydrate or prodrugs thereof in the oral cavity.Alternatively, a method of relieving or reducing oral pain of a subjectby administering a sublingual formulation comprising an effective amountof riluzole or a pharmaceutically acceptable salts, solvate, anomers,hydrate or prodrugs thereof.

Although the sublingual formulation may cause numbness or parathesias,the effect is normally nominal and well tolerated.

A treatment area of oral pain may be throughout an oral cavity includingthe upper surface of the tongue, lips, buccal area, back of throat,entire oral cavity or combinations thereof. In addition, the oral painfor treatment is caused by infection, inflammation, burn, cut,toothache, sore gums, canker sores, braces, minor dental procedures,denture irritation, oral surgery, neurologic disorders, disorders of themucosa, oral ulcers, chemotherapy agents or combinations thereof.

A therapeutic effect begins within about 30 min after administration,within 20 min after administration, within about 15 minute afteradministration, within about 10 min after administration, within about 5min after administration, within about 4 min after administration,within about 3 min after administration, within about 2 min afteradministration, or within about 1 min after administration.

The sublingual formulation for treating oral pain may be dosed at orbelow about 200 mg/day, at or below about 100 mg/day, at or below about70 mg/day, at or below about 50 mg/day, at or below about 42.5 mg/day,at or below about 37.5 mg mg/day, at or below about 35 mg/day, at orbelow about 20 mg/day, at or below about 15 mg/day, at or below about 10mg/day, or at or below about 5 mg/day.

According to various exemplary embodiments, the sublingual formulationmay have a greater C_(max) or greater dose normalized Cmax than theorally administered riluzole to provide a therapeutically beneficialeffect. Moreover, the sublingual formulation of the present inventionmay have a lesser or earlier T_(max) than orally administered riluzoleto provide a therapeutically beneficial effect. In addition, thesublingual formulation may have a greater AUC per milligram of theriluzole than the orally administered riluzole. The greater AUC permilligram may be measured in partial AUC0-0.5h, AUC0-1h, AUC0-2h,AUC0-12h, AUCo-t or AUC0-inf.

The present invention also provides a sublingual or sustained releaseformulation which may comprise an effective amount of riluzole or apharmaceutically acceptable salts, solvate, anomers, enantiomers,hydrate or prodrugs thereof to treat irritable bowel syndrome. Thepresent invention also provides a sublingual or sustained releaseformulation which may comprise an effective amount of riluzole or apharmaceutically acceptable salts, solvate, anomers, enantiomers,hydrate or prodrugs thereof to treat cancers such as gliomas,glioblastoma or melanoma. The present invention also provides asublingual or sustained release formulation which may comprise aneffective amount of riluzole or a pharmaceutically acceptable salts,solvate, anomers, enantiomers, hydrate or prodrugs thereof to treatcancers in combination with immunotherapies (including alone or incombination with vaccines, anti-PD1, anti-PDL1, anti-CTLA4 or otherimmunotherapy or checkpoint inhibitor targets including: CTLA4,cytotoxic T-lymphocyte-associated antigen 4; Ig, immunoglobulin; LAG3,lymphocyte activation gene 3; mAbs, monoclonal antibodies; PD1,programmed cell death protein 1; PDL, PD1 ligand; TIM3, T cell membraneprotein 3, CD40L, A2aR, adenosine A2a receptor; B7RP1, B7-relatedprotein 1; BTLA, B and T lymphocyte attenuator; GAL9, galectin 9; HVEM,herpesvirus entry mediator; ICOS, inducible T cell co-stimulator; IL,interleukin; KIR, killer cell immunoglobulin-like receptor, LAG3,lymphocyte activation gene 3; PD1, programmed cell death protein 1; PDL,PD1 ligand; TGFβ, transforming growth factor-β; TIM3, T cell membraneprotein 3; CD27).

Other aspects of the invention are disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present invention. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this disclosurebelongs. The terminology used in the description is for describingparticular embodiments only and is not intended to be limiting. Allpublications, patent applications, patents, figures and other referencesmentioned herein are expressly incorporated by reference in theirentirety.

The following terms are used to describe the present invention. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present invention.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The term “riluzole”, as used herein, refers to a drug having a chemicalstructure as follows. It is currently available in the market asRILUTEK®. The term “riluzole” also refers to all prodrugs, enantiomers,or derivatives and its pharmaceutically acceptable salts.

6-(trifluoromethoxy)benzothiazol-2-amine

The term “sublingual administration”, as used herein, refers to a routeof administrating a chemical agent or a drug by placing thereof under atongue of a subject.

The term “prodrug” as used herein, is a precursor of a drug which may beadministered in an altered or less active form. The prodrug may beconverted into the active drug form in physiological environments byhydrolysis or other metabolic pathways.

The term “riluzole prodrug” refers to a compound which is a derivativefrom riluzole with modification therein. A riluzole prodrug may alsorefer to a compound that is metabolized into an active form of riluzoleby the body.

The term “ALS”, as used herein, means Amyotrophic Lateral Sclerosis.

The term “neuropsychiatric disorder”, as used herein, is a mental orneurologic disorder which is associated with the nervous system. Forexample, the neuropsychiatric disorder may include anxiety disorders,mood disorders, neurodegenerative disorders, neurodevelopmentaldisorders, autism, pervasive developmental disorder, pain disorders,neuropathic pain. ALS, cognitive disorders, Huntington's disease,Parkinson's disease, supranuclear palsy, frontotemporal dementia,frontotemporal lobar degeneration, schizophrenia, delirium, Alzheimer'sdisease, mild cognitive impairment, mild cognitive impairment due toAlzheimer's disease, depression, mania, attention deficit disorders,drug addiction, dementia, agitation, apathy, anxiety, psychoses,post-traumatic stress disorders, irritability, and disinhibition,learning disorders, memory loss, mental retardation, dementia,personality disorders, bipolar disorders, bipolar depression,generalized anxiety disorder, panic disorder, obsessive-compulsivedisorders, trichotillomania, eating disorders, and the like. Morespecifically, neuropsychiatric disorders includes those listed in theDiagnostic and Statistical Manual of Mental Disorders (AmericanPsychiatric Association, 5^(th) Edition): Neurodevelopmental disorders.Intellectual disabilities, Intellectual disability (intellectualdevelopmental disorder), Global developmental delay, Unspecifiedintellectual disability (Intellectual developmental disorder).Communication disorders. Language disorder, Speech sound disorder.Childhood-onset fluency disorder (stuttering), Social (pragmatic)communication disorder. Unspecified communication disorder, Autismspectrum disorder, Rett Syndrome, Attention deficit hyperactivitydisorder (ADHD), Unspecified attention-deficit/Hyperactivity disorder,Specific learning disorder, Motor disorders, Developmental coordinationdisorder, Stereotypic movement disorder, Tic disorders, Tourette'sdisorder, Persistent (Chronic) motor or vocal tic disorder, Provisionaltic disorder, Other specified tic disorder, Unspecified tic disorder,Other neurodevelopmental disorders, Unspecified neurodevelopmentaldisorder, Schizophrenia spectrum and other psychotic disorders.Delusional disorder. Brief psychotic disorder, Schizophreniformdisorder, Schizophrenia, Schizoaffective disorder, Major depressive ormanic mood disorder concurrent with primary symptoms of schizophrenia,Substance/Medication-induced psychotic disorder, Psychotic disorder dueto another medical condition, Catatonia, Other specified schizophreniaspectrum and other psychotic disorder, Unspecified schizophreniaspectrum and other psychotic disorder, Bipolar and related disorders,Anxiety disorders, Obsessive-compulsive and related disorders, Trauma-and stressor-related disorders, Reactive attachment disorder,Disinhibited social engagement disorder, Posttraumatic stress disorder,Acute stress disorder, Adjustment disorder, Other specified Trauma- andstressor-related disorder, Unspecified trauma- and stressor-relateddisorder, Dissociative disorders, Dissociative identity disorder,Dissociative amnesia, Depersonalization/Derealization disorder, Somaticsymptom disorders, Encopresis, other elimination disorder, Disruptive,impulse-control and conduct disorders in DSM-5, Oppositional defiantdisorder, Intermittent explosive disorder, Conduct disorder, Otherspecified disruptive, conduct disorder, unspecified disruptive, andconduct disorder, Substance-Related and Addictive Disorders,Substance-Related Disorders, Alcohol-Related Disorders, Alcohol UseDisorder, Alcohol Withdrawal, Cannabis-Related Disorders, Cannabis UseDisorder, Gambling Disorder, Cluster A personality disorders, Paranoidpersonality disorder, Schizoid personality disorder, Schizotypalpersonality disorder, Cluster B personality disorders, Antisocialpersonality disorder, Borderline personality disorder, Histrionicpersonality disorder, Narcissistic personality disorder, Cluster Cpersonality disorders, Avoidant personality disorder, Dependentpersonality disorder, Obsessive-compulsive personality disorder,Paraphilic disorders.

The term “DSM” refers to a Diagnostic and Statistical Manual of MentalDisorders as provided by American Psychiatric Association's (APA)classification and diagnostic tool. Diagnostic and Statistical Manual ofMental Disorders. Fifth Edition (DSM-5 or DSM-V) is updated in 2013 andexemplary disorders in DSM-V are listed in Appendix A. In addition, theDSM-V has a structure that includes broad categories and subdiagnosesindicating disorders, conditions and problems.

“Neuropsychiatric disorders” could also include neurodegenerative orneurologic disorders including: Alzheimer's disease, dementia, vasculardementia, mixed dementia, Parkinson's disease, Huntington's disease.Amyotrophic lateral sclerosis (ALS), pseudobulbar affect, agitation inAlzheimer's disease, cerebellar ataxia, hereditary ataxias, multiplesclerosis, Progressive Supranuclear Palsy, pain disorders, neuropathicpain, neuropathies, stroke, seizure, Fragile X, tinnitus, and similarconditions.

The neuropsychiatric symptoms may include anxiety, depression, stress,fatigue, feelings of panic, fear, uneasiness, problems in sleeping, coldor sweaty hands and/or feet, shortness of breath, heart palpitations,social phobia, fear of public speaking, an inability to be still andcalm, dry mouth, numbness or tingling in the hands or feet, nausea,muscle tension, dizziness apathy, elation, disinhibition, irritability,wandering, and the like. Additionally, neuropsychiatric symptoms couldinclude: delusions, hallucinations, disorganized thinking or speech,derailment of focal topic or loose associations, incoherence, grosslydisorganized or abnormal motor behavior (including catatonia), negativesymptoms—reduced emotional expression, avolition, alogia, anhedonia,associality, dyskinesias (including tardive dyskinesia), anhedonia anddysphoria, anger and aggression, or symptoms of dissociation, or somecombination of these.

Other disorders treated could include cancer (including AcuteLymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML).Adrenocortical Carcinoms, Childhood cancers, AIDS-Related Cancers,Kaposi Sarcoma, AIDS-Related Lymphoma, Primary CNS Lymphoma, AnalCancer, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor, Basal CellCarcinoma, Skin Cancer (Nonmelanoma), Bile Duct Cancer, Bladder Cancer,Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and MalignantFibrous Histiocytoma, Brain Stem Glioma, Atypical Teratoid/RhabdoidTumor, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma,Ependymoma, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma,Non-Hodgkin Lymphoma, Carcinoid Tumor, Gastrointestinal Carcinoma,Cardiac (Heart) Tumors, Primary Lymphoma, Cervical Cancer,Cholangiocarcinoma, Chordoma, Chronic Lymphocytic Leukemia (CLL),Chronic Myelogenous Leukemia (CML), Chronic MyeloproliferativeNeoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, CutaneousT-Cell Lymphoma, Mycosis Fungoides and Sézary Syndrome, Ductal CarcinomaIn Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoma,Esophageal Cancer, Esthesioneuroblastoma, Extracranial Germ Cell Tumor,Extragonadal Germ Cell Tumor, Eye Cancer, Intraocular Melanoma,Retinoblastoma, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone,Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach)Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal StromalTumors (GIST), Germ Cell Tumor, Ovarian, Testicular, GestationalTrophoblastic Disease, Glioma, Hairy Cell Leukemia, Head and NeckCancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell,Hodgkin Lymphoma, Hypopharyngeal Cancer, Islet Cell Tumors, PancreaticNeuroendocrine Tumors, Kaposi Sarcoma, Kidney, Renal Cell, Wilms Tumor,Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, AcuteLymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL),Chronic Myelogenous (CML), Hairy Cell, Lip and Oral Cavity Cancer, LiverCancer (Primary), Lung Cancer, Non-Small Cell, Small Cell, Lymphoma,Hodgkin, Non-Hodgkin, Macroglobulinemia, Waldenström Male Breast Cancer,Melanoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous NeckCancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene,Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, MultipleMyeloma/Plasma Cell Neoplasm, Mycosis Fungoides, MyelodysplasticSyndromes, Myelodysplastic/Myeloproliferative Neoplasms, MyelogenousLeukemia, Chronic (CML), Myeloid Leukemia, Acute (AML) Myeloma,Multiple, Myeloproliferative Neoplasms, Nasal Cavity and Paranasal SinusCancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma,Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip andOropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma ofBone, Ovarian Cancer, Low Malignant Potential Tumor, Pancreatic Cancer,Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis,Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, ParathyroidCancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, PituitaryTumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma,Pregnancy and Breast Cancer, Primary Central Nervous System (CNS)Lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer,Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional CellCancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer,Rhabdomyosarcoma, Uterine, Small Intestine Cancer, Soft Tissue Sarcoma,Sqamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary,Metastatic, Ttomach (Gastric) Cancer, T-Cell Lymphoma, TesticularCancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer,Transitional Cell Cancer of the Renal Pelvis and Ureter, UnknownPrimary, Ureter and Renal Pelvis, Transitional Cell Cancer, UrethralCancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Vaginal Cancer,Vulvar Cancer, Waldenström Macroglobulinemia. Wilms Tumor.

The term “treatment” as used herein includes any treatment of acondition or disease in a subject, or particularly a human, and mayinclude: (i) preventing the disease or condition from occurring in thesubject which may be predisposed to the disease but has not yet beendiagnosed as having it; (ii) inhibiting the disease or condition, i.e.,arresting its development; relieving the disease or condition, i.e.,causing regression of the condition; or (iii) ameliorating or relievingthe conditions caused by the disease, i.e., symptoms of the disease.“Treatment,” as used herein, could be used in combination with otherstandard therapies or alone.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result.

The term “effective amount” refers to that amount which is sufficient toeffect treatment, as defined herein, when administered to a subject inneed of such treatment. The effective amount will vary depending on thesubject and disease state being treated, the severity of the afflictionand the manner of administration, and may be determined routinely by oneof ordinary skill in the art.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds or prodrugs described herein which are presented toincrease the solubility of the compound in the gastric or gastroentericjuices of the patient's gastrointestinal tract in order to promotedissolution and the bioavailability of the compounds. Pharmaceuticallyacceptable salts include those derived from pharmaceutically acceptableinorganic or organic bases and acids, where applicable. Suitable saltsinclude those derived from alkali metals such as potassium and sodium,alkaline earth metals such as calcium, magnesium and ammonium salts,among numerous other acids and bases well known in the pharmaceuticalart. Sodium and potassium salts are particularly preferred asneutralization salts of the phosphates according to the presentinvention. In a preferred embodiment, the description providespharmaceutically acceptable salts of the modified peptides as describedherein, which retain the biological effectiveness and properties of theparent compounds and which are not biologically or otherwise harmful asthe dosage administered. The compounds of this invention are capable offorming both acid and base salts by virtue of the presence of amino andcarboxy groups respectively.

The term “C_(max)”, as used herein, refers to a maximum concentration ofa drug in blood, serum, a specified compartment or test area of asubject between administration of a first dose and administration of asecond dose. The term Cmax could also refer to dose normalized ratios ifspecified.

The term “T_(max)”, as used herein, refers to a time or period afteradministration of a drug when the maximum concentration (C_(max)) isreached in blood, serum, a specified compartment or test area of asubject.

The term “AUC” (area under the curve), as used herein, refers to a totalamount of drug absorbed or exposed to a subject. Generally, AUC may beobtained from mathematical method in a plot of drug concentration in thesubject over time until the concentration is negligible. The term “AUC”(area under the curve) could also refer to partial AUC at specified timeintervals (as may be the case with sublingual absorption which wouldincrease AUC at earlier time intervals).

Sublingual Formulation of Riluzole

The invention relates to a sublingual formulation of riluzole. Thesublingual formulation may be administered in an effective amount to asubject in need thereof. The subject may be an animal or human.

According to the current invention, the riluzole or its pharmaceuticallyacceptable salts thereof may be formulated in a pharmaceuticalcomposition suitable for sublingual administration.

Riluzole and the pharmaceutically acceptable salts thereof can beformulated using pharmaceutically acceptable carriers well known in theart into dosages suitable for sublingual or buccal administration. Suchcarriers enable the riluzole for sublingual administration to beformulated in dosage forms such as tablets, powders, pills, capsules,liquids, gels, syrups, slurries, suspensions, and the like, forsublingual absorption by a subject to be treated. These carriers may be,but not limited to, selected from sugars, starches, cellulose and itsderivatives, malt, gelatin, talc, calcium sulphate, vegetable oils,synthetic oils, polyols, alginic acid, phosphate buffered solutions,emulsifiers, isotonic saline, pyrogen-free water and combinationsthereof. In particular, any form of substance may be accepted tosublingual administration if it dissolves easily in saliva.

The sublingually administered chemical agent or the drug can diffuseinto capillaries through mucous membrane under the tongue, and thenenter venous circulation of the subject. As such, sublingualadministration may have advantages over oral administration as allowingfor direct or faster entry to venous circulation, without risks ofdegradation in gastrointestinal tract, alteration by drug metabolism inliver and the like. Various drugs in the market are designed forsublingual administration. Riluzole is generally used to treatamyotrophic lateral sclerosis (ALS). However, other uses have beenfound, and in particular, riluzole or prodrugs of riluzole orpharmaceutically acceptable salts thereof is subjected to a sublingualadministration for the treatment of neuropsychiatric disorders. Thesublingual administration may also be used for other neuropsychiatricdisorders or relieving or reducing pain. In some instances, thepreferred effect is on oral pain.

The pharmaceutical composition may include an approved pharmaceuticalingredient, i.e., riluzole, in an effective amount to achieve theirintended purpose. For example, the dose of the riluzole administeredsublingually to the subject should be sufficient to provide a beneficialresponse in the subject over time such as reduction in symptoms.

The quantity of the riluzole to be administered may depend on thesubject to be treated inclusive of the age, sex, weight and generalhealth condition thereof. In this regard, precise amounts of theagent(s) for administration will depend on the judgement of thepractitioner. In determining the effective amount of the riluzole to beadministered in the treatment or reducing of the conditions associatedwith the neuropsychiatric symptoms and disorders, the physician mayevaluate clinical factors including symptoms severity or progression ofthe disorder. In some conditions, a rapid absorption of riluzole may bedesirable. In any event, those of skill in the art may readily determinesuitable dosages of the chemical agents of the invention.

The pharmaceutical composition also includes other pharmaceuticallyacceptable carriers and/or excipients such as binders, lubricants,diluents, coatings, disintegrants, barrier layer components, glidants,colouring agents, solubility enhancers, gelling agents, fillers,proteins, co-factors, emulsifiers, solubilising agents, suspendingagents and mixtures thereof. A skilled artisan in the art would knowwhat other pharmaceutically acceptable carriers and/or excipients couldbe included in the formulations according to the invention. The choiceof excipients would depend on the characteristics of the compositionsand on the nature of other pharmacologically active compounds in theformulation. Appropriate excipients are known to those skilled in theart (see Handbook Of Pharmaceutical Excipients, fifth edition, 2005edited by Rowe et al., McGraw Hill) and have been utilized to yield anovel sublingual formulation with unexpected properties.

In addition, the pharmaceutical composition for sublingual use can beobtained by combining the approved pharmaceutical ingredient, i.e.,riluzole, with further excipients, with optionally processing to obtaindosage forms such as tablets, powders, pills, capsules, liquids, gels,syrups, slurries, suspensions, and the like, for sublingual absorptionby a subject to be treated. Suitable excipients may be, but not limitedto, fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may becombined as well, and exemplary disintegrating agents may be, but notlimited to, cross-linked polyvinyl pyrrolidone, agar, or alginic acid ora salt thereof such as sodium alginate. The compositions may be preparedby any of the methods of pharmacy but all methods include the step ofbringing into association one or more chemical agents as described abovewith the carrier which constitutes one or more necessary ingredients. Ingeneral, the pharmaceutical compositions of the present invention may bemanufactured in conventional methods known in the art, for example, bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping, lyophilisingprocesses and the like.

The sublingual formulation of the invention may be prepared in a form ofan orally dissolving or disintegrating tablet (ODT). The ODT as usedherein may be prepared by mixing the riluzole with water-solublediluents and compressed in a tablet. For example, PHARMABURST® (SPIPharma, Wilmington, Del.) has been known as such an ODT preparationplatform. Alternatively, a suspension comprising riluzole may beprepared with appropriate excipients and the riluzole suspension may bedispensed into blister packs and freeze-dried. An exemplary freeze-driedpreparation platform that could be used for the riluzole ODT is theZYDIS® (Catalent, Somerset, N.J., USA) formulation. In particular, theexcipients, including water, are blended and the riluzole is separatelymilled to size and mixed with the excipients. The suspension thenundergoes lyophilisation by flash freezing and freeze drying. Othermethods of preparing ODTs may be used without limitation, and detaileddescription of general methods thereof have been disclosed, for example,in U.S. Pat. Nos. 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270;6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978;6,908,626; 6,908,626; 6,982,251; 7,282,217; 7,425,341; 7,939,105;7,993,674; 8,048,449; 8,127,516; 8,158,152; 8,221,480; 8,256,233; and8,313,768, each of which is incorporated herein by reference in itsentirety.

The sublingual formulation of the invention may comprise riluzole or aneffective amount of a riluzole prodrug. The riluzole prodrug may besimilar or less active form of riluzole. The riluzole prodrug may haveimproved physiochemical, physiological pharmacokinetic or therapeuticalcharacteristics when administered sublingually. The riluzole prodrug mayreduce side effects when orally or sublingually administered. Inparticular, the numbness or parethesias that can occur when riluzole isadministered orally that can occur sublingually may be reduced oreliminated by using the riluzole prodrug instead of riluzole.

Riluzole may also be formulated into a intranasal delivery system. Whilethis could be in the form of a “wet” spray, preferably the riluzole isdissolved in a solution and the solution is freeze dried and pulverizedor milled, if necessary, to form a powder-like formulation. Moreparticularly, the riluzole API is milled to the desired size and thecarrier and excipients are wet blended together. The riluzole is thenadded to the excipient mixture, the resulting solution or suspension isflash frozen then lyophilized to form a freezed dried product. Ifnecessary, the resulting freeze dried product is milled or otherwisepulverized to obtain the desired particle size. This powder-likeformulation can be loaded into multi-use inhalers or packaged intoindividual packets for use in single dose inhalers. The intranasaldelivery system may also make use of riluzole dissolved in solution orin suspension, loaded into an inhaler and packaged for individual ormultiple uses. Both the sublingual formulation and the intranasal spraybypass the gut, allowing a different absorption profile than an oraltablet.

The clinical or therapeutic effect of the riluzole sublinguallyformulated may have an improved pharmacokinetic profile for thepharmaceutical agent as measured by standard testing parameters. Whenthe riluzole is administered sublingually, the T_(max), C_(max) and AUCof the drug may be improved compared to the same dose of the orallyadministered riluzole. For example, the sublingual formulation of theriluzole may have a greater C_(max) than the orally administeredriluzole to provide a therapeutically beneficial effect. The sublingualformulation of the riluzole may have an earlier or lesser T_(max) thanthe orally administered riluzole to provide a therapeutically beneficialeffect and in some instances, a more rapid therapeutic effect.Alternatively, the sublingual formulation of the riluzole may have agreater AUC per milligram of the riluzole than the orally administeredriluzole.

Method of Treating a Disease

The invention also provides a method of treating a disease. The methodcomprises administering sublingually an effective amount of riluzole orpharmaceutically acceptable salts thereof to a subject in need thereof.

Identifying the subject in need of such treatment can be in the judgmentof the subject or a health care professional and can be subjective(e.g., opinion) or objective (e.g., measurable by a test or diagnosticmethod). The identified subject may be an animal or human in needthereof, particularly a human. Such treatment will be suitablyadministered to subjects, particularly humans, suffering from thedisease.

The disease from which the subject may be suffered may be aneuropsychiatric disorder or symptom. Exemplary neuropsychiatricdisorder may be anxiety disorders, mood disorders, neurodegenerativedisorders, pain disorders. ALS cognitive disorders, Huntington'sdisease, Parkinson's disease, supranuclear palsy, frontotemporaldementia, frontotemporal lobar degeneration, schizophrenia, delirium.Alzheimer's disease, mild cognitive impairment, mild cognitiveimpairment due to Alzheimer's disease, depression, mania, attentiondeficit disorders, drug addiction, dementia, agitation, apathy, anxiety,psychoses, post-traumatic stress disorders, irritability, anddisinhibition, learning disorders, memory loss, mental retardation,dementia, personality disorders, bipolar disorders, obsessive-compulsivedisorders, eating disorders, and the like. Exemplary neuropsychiatricsymptoms may be anxiety, depression, stress, fatigue, feelings of panic,fear, uneasiness, problems in sleeping, cold or sweaty hands and/orfeet, shortness of breath, heart palpitations, an inability to be stilland calm, dry mouth, numbness or tingling in the hands or feet, nausea,muscle tension, dizziness apathy, elation, disinhibition, irritability,wandering, or combinations thereof.

The effective amount of the riluzole may be determined by the degree ofa therapeutic effect, such as anxiolytic, antidepressant, moodstabilizing, stress resilient or stress relieving, anti-pain, orcombinations thereof. Further, the effect of sublingual administrationof riluzole may be also be indicated by unexpected and novel propertiesincluding, but not limited to: a) an attenuated or improved side effector tolerability profile compared to oral dosing; b) rapid onset oftherapeutic action; c) decreased liver function abnormalities; d) aunique pharmacokinetic profile compared to oral administration; e) alower therapeutic dose compared that typical oral dosing; f) once dailydosing; and g) minimized or absent oral parathesias or numbing.

The effective amount will vary depending on the subject and diseasestate being treated, the severity of the affliction and the manner ofadministration, and may be determined routinely by one of ordinary skillin the art.

The therapeutic effect of the riluzole may be evident to occur withinabout a few minutes to about an hour after sublingual administrationthereof. In particular, the therapeutic effect may begin within about 1minute, within about 2 minutes, within about 3 minutes, within about 4minutes, within about 5 minutes, within about 6 minutes, within about 7minutes, within about 8 minutes, within about 9 minutes, within about 10minutes, within about 11 minutes, within about 12 minutes, within about13 minutes, within about 14 minutes, within about 15 minutes, withinabout 16 minutes, within about 17 minutes, within about 18 minutes,within about 20 minutes, within about 60 minutes, or within about 90minutes after administration.

The effects of the riluzole may be maintained for about 1 hour, forabout 2 hours, for about 3 hours, for about 4 hours, for about 5 hours,for about 6 hours m for about 7 hours, for about 8 hours, for about 9hours, for about 10 hours, for about 12 hours, for about 14 hours, forabout 16 hours, for about 18 hours, for about 20 hours, for about 22hours, for about 24 hours, for about 2 days, or for about 3 days or moreafter sublingual administration thereof.

The effective amount or dose of riluzole for sublingual administrationmay be less than that of orally administered riluzole. In particular,the effective dose in sublingual administration of riluzole may be ofabout 1-95% of the dose of the orally administered riluzole.

The effective amount of the riluzole or pharmaceutically acceptablesalts thereof in sublingual administration for treatment ofneuropsychiatric disorders may be dosed at or less than about 200mg/day, at or less than about 100 mg/day, at or less than about 90mg/day, at or less than about 80 mg/day, at or less than about 70mg/day, at or less than about 60 mg/day, at or less than about 50mg/day, at or less than about 40 mg/day, at or less than about 37.5mg/day, at or less than about 35 mg/day, at or less than about 30mg/day, at or less than about 20 mg/day, at or less than about 17.5mg/day, at or less than about 15 mg/day, at or less than about 10mg/day, at or less than about 9 mg/day, at or less than about 8 mg/day,at or less than about 7 mg/day, at or less than about 6 mg/day, at orless than about 5 mg/day, at or less than about 4 mg/day, at or lessthan about 3 mg/day, at or less than about 2 mg/day, or at or less thanabout 1 mg/day.

Optional dosage frequencies include once a day, twice a day, three timesa day, four times a day, once every other day, once a week, twice aweek, three times a week, four times a week, once every two weeks, onceor twice monthly, and the like.

The clinical or therapeutic effect of the riluzole sublinguallyformulated and administered for neuropsychiatric disorders or symptomsmay have an improved pharmacokinetic profile for the pharmaceuticalagent as measured by standard testing parameters. When the riluzole isadministered sublingually, the T_(max), C_(max) or AUC of the drug maybe improved compared to the same dose of the orally administeredriluzole. For example, the sublingual administration of the riluzole mayhave a greater C_(max) than the orally administered riluzole to providea therapeutically beneficial effect. The sublingual administration ofthe riluzole has a less T_(max) than the orally administered riluzole toprovide a therapeutically beneficial effect. Alternatively, thesublingual administration of the riluzole may have a greater AUC permilligram of the riluzole than the orally administered riluzole.

In some embodiments, the orally disintegrating formulation would be aprodrug that could be sublingually administered or even orally dispersedthen swallowed with enhanced pharmacokinetic properties.

Sublingual Formulation for Oral Pain

The current invention further includes a method of sublinguallyadministering the riluzole to the subject to produce other desiredeffects.

A method is provided of relieving or reducing oral pain by sublingualadministration of riluzole. The method comprises administering asublingual formulation having an effective amount of riluzole to asubject in need thereof. In certain embodiments, the subject may be ananimal or human.

In certain embodiments, the sublingual formulation may induce numbnessfrom the deposition site thereof. The numbness may be effective toreduce or relieve oral pain and spread throughout the mucosal contacts.A level of numbness may be in a tolerable range to the subject.

A treatment area of oral pain may be, but not limited to, throughout anoral cavity including the upper surface of the tongue, lips, buccalarea, back of throat, entire oral cavity and the like. The oral pain fortreatment may be caused by infection, viruses, inflammation, burn, cut,toothache, sore gums, canker sores, braces, minor dental procedures,denture irritation, oral surgery, neurologic disorders, disorders of themucosa or caused by other drugs known to induce painful oral ulcers(such as chemotherapy agents).

The effects of reducing oral pain may occur within a minute or about afew minutes to about an hour. In particular, the numbness may beginwithin about 1 minute, within about 2 minutes, within about 3 minutes,within about 4 minutes, within about 5 minutes, within about 6 minutes,within about 7 minutes, within about 8 minutes, within about 9 minutes,within about 10 minutes, within about 11 minutes, within about 12minutes, within about 13 minutes, within about 14 minutes, within about15 minutes, within about 16 minutes, within about 17 minutes, or withinabout 18 minutes, within about 19 minutes, or within about 20 minutesafter administration.

The effects of relieving or reducing oral pain may be maintained forabout 1 hour, for about 2 hours, for about 3 hours, for about 4 hours,for about 5 hours, for about 6 hours m for about 7 hours, for about 8hours, for about 9 hours, for about 10 hours, for about 12 hours, forabout 14 hours, for about 16 hours, for about 18 hours, for about 20hours, for about 22 hours, for about 24 hours, for about 2 days, or forabout 3 days after sublingual administration thereof.

The sublingual administration of riluzole for relieving or reducing oralpain may be dosed at or less than about 200 mg/day, at or less thanabout 100 mg/day, at or less than about 90 mg/day, at or less than about80 mg/day, at or less than about 70 mg/day, at or less than about 60mg/day, at or less than about 50 mg/day, at or less than about 40mg/day, at or less than about 35 mg/day, at or less than about 30mg/day, at or less than about 20 mg/day, at or less than about 17.5mg/day, at or less than about 10 mg/day, at or less than about 9 mg/day,at or less than about 8 mg/day, at or less than about 7 mg/day, at orless than about 6 mg/day, at or less than about 5 mg/day, at or lessthan about 4 mg/day, at or less than about 3 mg/day, at or less thanabout 2 mg/day, or at or less than about 1 mg/day.

Optional dosage frequencies include once a day, twice a day, three timesa day, four times a day, once a week, twice a week, three times a week,four times a week, once every two weeks, once or twice monthly, and thelike.

The formulation for relieving or reducing oral pain may comprise aneffective amount of riluzole and a pharmaceutically acceptable carrierthereof. The pharmaceutical composition can be formulated as tablets,powders, pills, capsules, liquids, gels, ointments, syrups, slurries,suspensions, and the like, to provide substantial absorption rate at thetreated area. An additional bioactive agent or other drugs may be addedto a pharmaceutical composition for effective and elevated effects ofpain relief. In some embodiments the formulation may be administeredtopically in the oral cavity or buccal mucosa.

EXAMPLES

The following examples illustrate the invention and are not intended tolimit the scope of the invention.

Example 1

A 51 year-old male was administrated with riluzole on four occasions.

(1) A normally orally administered form of riluzole was used as acomparator. A standard 50 mg riluzole tablet (a tablet not of thepresent invention) was pulverized and administered into the mouth cavityfor 40 seconds to allow for transmucosal and/or oral absorption. Thiswas not sublingual or buccal administration. There were no acute orchronic effects on neuropsychiatic domains. More specifically, therewere no effects on mood, anxiety or behavior. Prominent oral numbnesswas noted. Within the first minute, a sensation of numbness spreadthroughout the oral cavity including the upper surface of the tongue andlips, resulting in circumoral paresthesias. The effects were moderateand peaked within 4 minutes. The effects lasted for up to 80 minutes.The effects started subsiding after 15 minutes and were considered mildafter 40 minutes and minimal after 80 minutes. All effects were limitedto local mouth-related sensations described above.

(2) Separately, a first sublingual administration of a formulation ofthe invention was performed. About 70 mg of the sublingual formulationof riluzole was placed under the tongue of the subject and held firmlyin place. Unexpectedly, the subject experienced acute psychotropiceffects shortly after the sublingual administration. Withinapproximately 40 minutes from the sublingual administration, the subjectexperienced a sense of enhanced or improved mood. The subject noted asense of well-being and conveyed a sense of optimism that represented achange from the baseline mood state. The mood state change was estimatedto last for at least four hours.

Within one minute of sublingual administration, tongue numbnessdeveloped, and, after 4 minutes, numbness spread over the lips as wellas the back of the throat. The numbness reached to a moderate level in16 minutes, lessened to a mild level by 20 minutes, and fully dissipatedover the next hour. The numbness associated with the sublingualadministration was significantly attenuated compared to the diffuse oralpulverized administration described previously. The sublingualformulation yielded a mild and not bothersome numbness that waslocalized (versus the pulverized riluzole tablet that was more intense,bothersome and generalized).

(3) A second sublingual administration occurred on another day. About 70mg of a sublingual formulation of riluzole was placed under the tongueof the subject for about 95 seconds until fully dissolved. Again, thesubject experienced a similar improvement in mood. The subject reporteda sense of optimism and well-being. These feelings peaked by 40 minutes.After 25 minutes, the subject reported feeling relaxed (less anxious)and with an increased level of alertness. The subject reported improvedsleep condition and vivid dreams that evening.

Tongue and lip numbness was noted after about 4 minutes, peaked after 6minutes with a moderate level of numbness and waned thereafter to a mildlevel by about 24 minutes. The mouth numbness was considered very mildto minimal at this time point. Again, the oral numbness was attenuatedcompared to the diffuse oral administration of the pulverized standardriluzole tablet. No sedation was recognized.

(4) A third sublingual administration was tried with a lower dose of thesublingual formulation. About 30 mg of a sublingual formulation ofriluzole was placed under the tongue of the subject. Once again, acuteeffects (within 25 minutes) of the sublingual riluzole administrationwere observed and included the subject feeling relaxed, having a feelingof wellbeing, optimism, and alertness. Similar oral numbness to theprevious sublingual administrations was reported but attenuated comparedto the oral administration.

Example 2

A 43 year old male administered with riluzole on two occasions.

(1) An oral administration: About 50 mg of an unpulverized riluzoletablet (a formulation not of the invention) was placed on a tongue ofthe subject. No psychoactive effect was reported but immediately uponapplication, the subject reported numbness in the local area ofapplication that spread quickly throughout the entire oral cavity.Numbness lasted past 20 minutes. No mood or behavioral sensation wasreported. The numbness was intense and bothersome.

(2) A sublingual administration: About 20 mg of a sublingual formulationof riluzole was place under the tongue of the subject for about 30seconds. Within about 20 minutes, the subject reported the onset ofbeneficial psychoactive effects including feeling relaxed, calm and lessanxious. The subject also reported the sensation of feeling alert. Thesepsychoactive effects or feelings persisted for about 90 minutes. Thesubject noted that his stomach and gut felt “calm” and previous upsetstomach was lessened. The subject reported improved sleep condition thatevening.

Within a minute of application, the subject reported that numbness intongue and mouth reached a peak by about 7 minutes with moderate effect.The numbness started waning significantly after about 18 minutes to verymild by about 24 minutes. The numbness associated with the sublingualadministration was noted to be attenuated compared to the oraladministration in this subject. Overall, the numbness was very mild andnot bothersome with good mouth palatability compared to the pulverizedstandard riluzole (which was intense, bothersome, generalized and withpoor mouth palatability).

Example 3

A 50 year old male was administered with a sublingual formulation ofriluzole.

About 5 mg sublingual formulation of riluzole was placed under thetongue of the subject for about 20 seconds until the formulation wasfully dissolved. Again, as in the other subjects who received thesublingual administration, there were previously unexpected psychotropiceffects soon after administration. Within 20 to 30 minutes, the subjectreported the onset of beneficial psychoactive effects and he reported afeeling of relaxation and calm.

After about 7 minutes of administration, the subject reported numbnesson the roof of his mouth and tongue that peaked around about 7 minutes,and then was completely gone after about 21 minutes.

Example 4

A 57 year old male was administered with a sublingual formulation ofriluzole.

About 70 mg sublingual formulation of riluzole was placed under thetongue of the subject for about 74 seconds. Within about 24 minutes, thesubject reported psychoactive effects that were characterized by afeeling of being relaxed and alert that endured through about an hour.The subject reported that he felt so relaxed that he took a restful nap.The subject also reported that his stomach felt relaxed.

After 2 minutes of administration, the subject reported feelings ofnumbness on the tongue. Peak of mouth numbness occurred after about 4minutes and numbness waned to mild level after about 15 minutes. Again,compared to the subjects who received oral administration of riluzole,the sublingual administration was associated with an attenuated oralnumbness and parathesias.

Example 5

In this example, three sublingual formulations of riluzole were testedfor pharmokinetic properties against a commercially available 50 mgriluzole tablet. Partial AUC values. AUC0-0.5, AUC0-1. AUC0-, andAUC0-12 (being AUC values measured for 0.5 hours, 1 hour, 2 hours and 12hours after the dose was given) were measured and the ratios of thevalues for the test materials to the 50 mg oral dose were determined. Ascan be seen from the Table, the values from the sublingual formulationwere higher than a weight adjusted value of the oral dosage for all thedoses, particularly at the earlier times. The predicted ratios (assumingthat the sublingual and oral formulation reached the circulation at thesame rate) would be 20% for the 10 mg version, 35% for the 17.5 mgversion, and 70% for the 35 mg version.

Parameter Treatment Comparison Ratio AUC_(0-0.5) 10 mg sublingual v. 50mg  36.19% oral   17.5 mg sublingual v. 50  82.16% mg oral 35 mgsublingual v. 50 mg 180.84% oral AUC₀₋₁ 10 mg sublingual v. 50 mg 29.93% oral   17.5 mg sublingual v. 50  65.26% mg oral 35 mg sublingualv. 50 mg 136.20% oral AUC₀₋₂ 10 mg sublingual v. 50 mg  26.28% oral  17.5 mg sublingual v. 50  53.91% mg oral 35 mg sublingual v. 50 mg110.28% oral AUC₀₋₁₂ 10 mg sublingual v. 50 mg  22.47% oral   17.5 mgsublingual v. 50  43.38% mg oral   35 mg sublingual v. 50 mg  89.89%oral

As is evident from the Table, the sublingual formulations achieved amuch higher AUC value than predicted at the earlier times and it is onlyat 12 hours that the values are near (but still higher) that the weightpercent ratios. This shows that the sublingual formulation is beingadsorbed and not merely swallowed.

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of this invention and are covered by the followingclaims.

APPENDIX A ICD- ICD- 9-CM 10-CM Disorder, condition, or problem V62.3Z55.9 Academic or educational problem V62.4 Z60.3 Acculturationdifficulty 308.3 F43.0 Acute stress disorder Adjustment disorders 309.24F43.22 With anxiety 309.0 F43.21 With depressed mood 309.3 F43.24 Withdisturbance of conduct 309.28 F43.23 With mixed anxiety and depressedmood 309.4 F43.25 With mixed disturbance of emotions and conduct 309.9F43.20 Unspecified V71.01 Z72.811 Adult antisocial behavior 307.0 F98.5Adult-onset fluency disorder Adult physical abuse by nonspouse ornonpartner, Confirmed 955.81 T74.11XA Initial encounter 955.81 T74.11XDSubsequent encounter Adult physical abuse by nonspouse or nonpartner,Suspected 995.81 T76.11XA Initial encounter 995.81 T76.11XD Subsequentencounter Adult psychological abuse by nonspouse or nonpartner,Confirmed 995.82 T74.31XA Initial encounter 995.82 T74.31XD Subsequentencounter Adult psychological abuse by nonspouse or nonpartner,Suspected 995.82 T76.31XA Initial encounter 995.82 T76.31XD Subsequentencounter Adult sexual abuse by nonspouse or nonpartner, Confirmed995.83 T74.21XA Initial encounter 995.83 T74.21XD Subsequent encounterAdult sexual abuse by nonspouse or nonpartner, Suspected 995.83 T76.21XAInitial encounter 995.83 T76.21XD Subsequent encounter 300.22 F40.00Agoraphobia 291.89 Alcohol-induced anxiety disorder F10.180 With milduse disorder F10.280 With moderate or severe use disorder F10.980Without use disorder 291.89 Alcohol-induced bipolar and related disorderF10.14 With mild use disorder F10.24 With moderate or severe usedisorder F10.94 Without use disorder 291.89 Alcohol-induced depressivedisorder F10.14 With mild use disorder F10.24 With moderate or severeuse disorder F10.94 Without use disorder 291.1 Alcohol-induced majorneurocognitive disorder, Amnestic confabulatory type F10.26 Withmoderate or severe use disorder F10.96 Without use disorder 291.2Alcohol-induced major neurocognitive disorder, Nonamnestic confabulatorytype F10.27 With moderate or severe use disorder F10.97 Without usedisorder 291.89 Alcohol-induced mild neurocognitive disorder F10.288With moderate or severe use disorder F10.988 Without use disorder 291.9Alcohol-induced psychotic disorder F10.159 With mild use disorderF10.259 With moderate or severe use disorder F10.959 Without usedisorder 291.89 Alcohol-induced sexual dysfunction F10.181 With mild usedisorder F10.281 With moderate or severe use disorder F10.981 Withoutuse disorder 291.82 Alcohol-induced sleep disorder F10.182 With mild usedisorder F10.282 With moderate or severe use disorder F10.982 Withoutuse disorder 303.00 Alcohol intoxication F10.129 With mild use disorderF10.229 With moderate or severe use disorder F10.929 Without usedisorder 291.0 Alcohol intoxication delirium F10.121 With mild usedisorder F10.221 With moderate or severe use disorder F10.921 Withoutuse disorder Alcohol use disorder 305.00 F10.10 Mild 303.90 F10.20Moderate 303.90 F10.20 Severe 291.81 Alcohol withdrawal F10.232 Withperceptual disturbances F10.239 Without perceptual disturbances 291.0F10.231 Alcohol withdrawal delirium 292.89 Amphetamine (or otherstimulant)-induced anxiety disorder F15.180 With mild use disorderF15.280 With moderate or severe use disorder F15.980 Without usedisorder 292.84 Amphetamine (or other stimulant)-induced bipolar andrelated disorder F15.14 With mild use disorder F15.24 With moderate orsevere use disorder F15.94 Without use disorder F15.921 Amphetamine (orother stimulant)-induced delirium 292.84 Amphetamine (or otherstimulant)-induced depressive disorder F15.14 With mild use disorderF15.24 With moderate or severe use disorder F15.94 Without use disorder292.89 Amphetamine (or other stimulant)-induced obsessive-compulsive andrelated disorder F15.188 With mild use disorder F15.288 With moderate orsevere use disorder F15.988 Without use disorder 292.9 Amphetamine (orother stimulant)-induced psychotic disorder F15.159 With mild usedisorder F15.259 With moderate or severe use disorder F15.959 Withoutuse disorder 292.89 Amphetamine (or other stimulant)-induced sexualdysfunction F15.181 With mild use disorder F15.281 With moderate orsevere use disorder F15.981 Without use disorder 292.85 Amphetamine (orother stimulant)-induced sleep disorder F15.182 With mild use disorderF15.282 With moderate or severe use disorder F15.982 Without usedisorder 292.89 Amphetamine or other stimulant intoxication Amphetamineor other stimulant intoxication, With perceptual disturbances F15.122With mild use disorder F15.222 With moderate or severe use disorderF15.922 Without use disorder Amphetamine or other stimulantintoxication, Without perceptual disturbances F15.129 With mild usedisorder F15.229 With moderate or severe use disorder F15.929 Withoutuse disorder 292.81 Amphetamine (or other stimulant) intoxicationdelirium F15.121 With mild use disorder F15.221 With moderate or severeuse disorder F15.921 Without use disorder 292.0 F15.23 Amphetamine orother stimulant withdrawal Amphetamine-type substance use disorder305.70 F15.10 Mild 304.40 F15.20 Moderate 304.40 F15.20 Severe 307.1Anorexia nervosa F50.02 Binge-eating/purging type F50.01 Restrictingtype Antidepressant discontinuation syndrome 995.29 T43.205A Initialencounter 995.29 T43.205S Sequelae 995.29 T43.205D Subsequent encounter301.7 F60.2 Antisocial personality disorder 293.84 F06.4 Anxietydisorder due to another medical conditionAttention-deficit/hyperactivity disorder 314.01 F90.2 Combinedpresentation 314.01 F90.1 Predominantly hyperactive/impulsivepresentation 314.00 F90.0 Predominantly inattentive presentation 299.00F84.0 Autism spectrum disorder 301.82 F60.6 Avoidant personalitydisorder 307.59 F50.8 Avoidant/restrictive food intake disorder 307.51F50.8 Binge-eating disorder Bipolar I disorder, Current or most recentepisode depressed 296.56 F31.76 In full remission 296.55 F31.75 Inpartial remission 296.51 F31.31 Mild 296.52 F31.32 Moderate 296.53 F31.4Severe 296.54 F31.5 With psychotic features 296.50 F31.9 Unspecified296.40 F31.0 Bipolar I disorder, Current or most recent episodehypomanic 295.46 F31.72 In full remission 296.45 F31.71 In partialremission 296.40 F31.9 Unspecified Bipolar I disorder, Current or mostrecent episode manic 296.46 F31.74 In full remission 296.45 F31.73 Inpartial remission 296.41 F31.11 Mild 296.42 F31.12 Moderate 296.43F31.13 Severe 296.44 F31.2 With psychotic features 296.40 F31.9Unspecified 296.7 F31.9 Bipolar I disorder, Current or most recentepisode unspecified 296.89 F31.81 Bipolar II disorder 293.83 Bipolar andrelated disorder due to another medical condition F06.33 With manicfeatures F06.33 With manic- or hypomanic-like episodes F06.34 With mixedfeatures 300.7 F45.22 Body dysmorphic disorder V62.89 R41.83 Borderlineintellectual functioning 301.83 F60.3 Borderline personality disorder298.8 F23 Brief psychotic disorder 307.51 F50.2 Bulimia nervosa 292.89Caffeine-induced anxiety disorder F15.180 With mild use disorder F15.280With moderate or severe use disorder F15.980 Without use disorder 292.85Caffeine-induced sleep disorder F15.182 With mild use disorder F15.282With moderate or severe use disorder F15.982 Without use disorder 305.90F15.929 Caffeine intoxication 292.0 F15.93 Caffeine withdrawal 292.89Cannabis-induced anxiety disorder F12.180 With mild use disorder F12.280With moderate or severe use disorder F12.980 Without use disorder 292.9Cannabis-induced psychotic disorder F12.159 With mild use disorderF12.259 With moderate or severe use disorder F12.959 Without usedisorder 292.85 Cannabis-induced sleep disorder F12.188 With mild usedisorder F12.288 With moderate or severe use disorder F12.988 Withoutuse disorder 292.89 Cannabis intoxication Cannabis intoxication, Withperceptual disturbances F12.122 With mild use disorder F12.222 Withmoderate or severe use disorder F12.922 Without use disorder Cannabisintoxication, Without perceptual disturbances F12.129 With mild usedisorder F12.229 With moderate or severe use disorder F12.929 Withoutuse disorder 292.81 Cannabis intoxication delirium F12.121 With mild usedisorder F12.221 With moderate or severe use disorder F12.921 Withoutuse disorder Cannabis use disorder 305.20 F12.10 Mild 304.30 F12.20Moderate 304.30 F12.20 Severe 292.0 F12.288 Cannabis withdrawal 293.89F06.1 Catatonia associated with another mental disorder (catatoniaspecifier) 293.89 F06.1 Catatonic disorder due to another medicalcondition Central sleep apnea 780.57 G47.37 Central sleep apnea comorbidwith opioid use 786.04 R06.3 Cheyne-Stokes breathing 327.21 G47.31Idiopathic central sleep apnea V61.29 Z62.898 Child affected by parentalrelationship distress Child neglect, Confirmed 995.52 T74.02XA Initialencounter 995.52 T74.02XD Subsequent encounter Child neglect, Suspected995.52 T76.02XA Initial encounter 995.52 T76.02XD Subsequent encounterV71.02 Z72.810 Child or adolescent antisocial behavior Child physicalabuse, Confirmed 995.54 T74.12XA Initial encounter 995.54 T74.12XDSubsequent encounter Child physical abuse, Suspected 995.54 T76.12XAInitial encounter 995.54 T76.12XA Subsequent encounter Childpsychological abuse, Confirmed 995.51 T74.32XA Initial encounter 995.51T74.32XD Subsequent encounter Child psychological abuse, Suspected995.51 T76.32XA Initial encounter 995.51 T76.32XD Subsequent encounterChild sexual abuse, Confirmed 995.53 T74.22XA Initial encounter 995.53T74.22XD Subsequent encounter Child sexual abuse, Suspected 995.53T76.22XA Initial encounter 995.53 T76.22XD Subsequent encounter 315.35F80.81 Childhood-onset fluency disorder (stuttering) Circadian rhythmsleep-wake disorders 307.45 G47.22 Advanced sleep phase type 307.45G47.21 Delayed sleep phase type 307.45 G47.23 Irregular sleep-wake type307.45 G47.24 Non-24-hour sleep-wake type 307.45 G47.26 Shift work type307.45 G47.20 Unspecified type 292.89 Cocaine-induced anxiety disorderF14.180 With mild use disorder F14.280 With moderate or severe usedisorder F14.980 Without use disorder 292.84 Cocaine-induced bipolar andrelated disorder F14.14 With mild use disorder F14.24 With moderate orsevere use disorder F14.94 Without use disorder 292.84 Cocaine-induceddepressive disorder F14.14 With mild use disorder F14.24 With moderateor severe use disorder F14.94 Without use disorder 292.89Cocaine-induced obsessive-compulsive and related disorder F14.188 Withmild use disorder F14.288 With moderate or severe use disorder F14.988Without use disorder 292.9 Cocaine-induced psychotic disorder F14.159With mild use disorder F14.259 With moderate or severe use disorderF14.959 Without use disorder 292.89 Cocaine-induced sexual dysfunctionF14.181 With mild use disorder F14.281 With moderate or severe usedisorder F14.981 Without use disorder 292.85 Cocaine-induced sleepdisorder F14.182 With mild use disorder F14.282 With moderate or severeuse disorder F14.982 Without use disorder 292.89 Cocaine intoxicationCocaine intoxication, With perceptual disturbances F14.122 With mild usedisorder F14.222 With moderate or severe use disorder F14.922 Withoutuse disorder Cocaine intoxication, Without perceptual disturbancesF14.129 With mild use disorder F14.229 With moderate or severe usedisorder F14.929 Without use disorder 292.81 Cocaine intoxicationdelirium F14.121 With mild use disorder F14.221 With moderate or severeuse disorder F14.921 Without use disorder Cocaine use disorder 305.60F14.10 Mild 304.20 F14.20 Moderate 304.20 F14.20 Severe 292.0 F14.23Cocaine withdrawal Conduct disorder 312.82 F91.2 Adolescent-onset type312.81 F91.1 Childhood-onset type 312.89 F91.9 Unspecified onset 300.11Conversion disorder (functional neurological symptom disorder) F44.4With abnormal movement F44.6 With anesthesia or sensory loss F44.5 Withattacks or seizures F44.7 With mixed symptoms F44.6 With special sensorysymptoms F44.4 With speech symptoms F44.4 With swallowing symptoms F44.4With weakness/paralysis V62.5 Z65.0 Conviction in civil or criminalproceedings without imprisonment 301.13 F34.0 Cyclothymic disorder302.74 F52.32 Delayed ejaculation Delirium 293.0 F05 Delirium due toanother medical condition 293.0 F05 Delirium due to multiple etiologies292.81 Medication-induced delirium (for ICD-10-CM codes, see specificsubstances) Substance intoxication delirium (see specific substances forcodes) Substance withdrawal delirium (see specific substances for codes)247.1 F22 Delusional disorder 301.6 F60.7 Dependent personality disorder300.6 F48.1 Depersonalization/derealization disorder 293.83 Depressivedisorder due to another medical condition F06.31 With depressivefeatures F06.32 With major depressive-like episode F06.34 With mixedfeatures 315.4 F82 Developmental coordination disorder V60.89 Z59.2Discord with neighbor, lodger, or landlord V62.89 Z64.4 Discord withsocial service provider, including probation officer, case manager, orsocial services worker 313.89 F94.2 Disinhibited social engagementdisorder V61.03 Z63.5 Disruption of family by separation or divorce296.99 F34.8 Disruptive mood dyregulation disorder 300.12 F44.0Dissociative amnesia 300.13 F44.1 Dissociative amnesia, withdissociative fugue 300.14 F44.81 Dissociative identity disorder 307.7F98.1 Encopresis 307.6 F98.0 Enuresis 302.72 F52.21 Erectile disorder698.4 L98.1 Excoriation (skin-picking) disorder 302.4 F65.2Exhibitionistic disorder V62.22 Z65.5 Exposure to disaster, war, orother hostilities V60.2 Z59.5 Extreme poverty 300.19 F68.10 Factitiousdisorder 302.73 F52.31 Female orgasmic disorder 302.72 F52.22 Femalesexual interest/arousal disorder 302.81 F65.0 Fetishistic disorder302.89 F65.81 Frotteuristic disorder 312.31 F63.0 Gambling disorder302.85 F64.1 Gender dysphoria in adolescents and adults 302.6 F64.2Gender dysphoria in children 300.02 F41.1 Generalized anxiety disorder302.76 F52.6 Genito-pelvic pain/penetration disorder 315.8 F88 Globaldevelopmental delay 292.89 F16.983 Hallucinogen persisting perceptiondisorder V61.8 Z63.8 High expressed emotion level within family 301.50F60.4 Histrionic personality disorder 300.3 F42 Hoarding disorder V60.0Z59.0 Homelessness 307.44 F51.11 Hypersomnolence disorder 300.7 F45.21Illness anxiety disorder V62.5 Z65.1 Imprisonment or other incarcerationV60.1 Z59.1 Inadequate housing 292.89 Inhalant-induced anxiety disorderF18.180 With mild use disorder F18.280 With moderate or severe usedisorder F18.980 Without use disorder 292.84 Inhalant-induced depressivedisorder F18.14 With mild use disorder F18.24 With moderate or severeuse disorder F18.94 Without use disorder 292.82 Inhalant-induced majorneurocognitive disorder F18.17 With mild use disorder F18.27 Withmoderate or severe use disorder F18.97 Without use disorder 292.89Inhalant-induced mild neurocognitive disorder F18.188 With mild usedisorder F18.288 With moderate or severe use disorder F18.988 Withoutuse disorder 292.9 Inhalant-induced psychotic disorder F18.159 With milduse disorder F18.259 With moderate or severe use disorder F18.959Without use disorder 292.89 Inhalant intoxication F18.129 With mild usedisorder F18.229 With moderate or severe use disorder F18.929 Withoutuse disorder 292.81 Inhalant intoxication delirium F18.121 With mild usedisorder F18.221 With moderate or severe use disorder F18.921 Withoutuse disorder Inhalant use disorder 305.90 F18.10 Mild 304.60 F18.20Moderate 304.60 F18.20 Severe 307.42 F51.01 Insomnia disorder V60.2Z59.7 Insufficient social insurance or welfare support Intellectualdisability (intellectual developmental disorder) 317 F70 Mild 318.0 F71Moderate 318.1 F72 Severe 318.2 F73 Profound 312.34 F63.81 Intermittentexplosive disorder 312.32 F63.2 Kleptomania V60.2 Z59.4 Lack of adequatefood or safe drinking water 315.32 F80.2 Language disorder V60.2 Z59.6Low income Major depressive disorder, Recurrent episode 296.36 F33.42 Infull remission 296.35 F33.41 In partial remission 296.31 F33.0 Mild296.32 F33.1 Moderate 296.33 F33.2 Severe 296.34 F33.3 With psychoticfeatures 296.30 F33.9 Unspecified Major depressive disorder, Singleepisode 296.26 F32.5 In full remission 296.25 F32.4 In partial remission296.21 F32.0 Mild 296.22 F32.1 Moderate 296.23 F32.2 Severe 296.24 F32.3With psychotic features 296.20 F32.9 Unspecifed 331.9 G31.9 Majorfrontotemporal neurocognitive disorder, Possible Major frontotemporalneurocognitive disorder, Probable (code first 331.19 [G31.09]frontotemporal disease) 294.11 F02.81 With behavioral disturbance 294.10F02.80 Without behavioral disturbance 331.9 G31.9 Major neurocognitivedisorder due to Alzheimer's disease, Possible Major neurocognitivedisorder due to Alzheimer's disease, Probable (code first 331.0 [G30.9]Alzheimer's disease 294.11 F02.81 With behavioral disturbance 294.10F02.80 Without behavioral disturbance Major neurocognitive disorder dueto another medical condition 294.11 F02.81 With behavioral disturbance294.10 F02.80 Without behavioral disturbance Major neurocognitivedisorder due to HIV infection (code first 042 [B20] HIV infection)294.11 F02.81 With behavioral disturbance 294.10 F02.80 Withoutbehavioral disturbance Major neurocognitive disorder due to Huntington'sdisease (code first 333.4 [G10] Huntington's disease) 294.11 F02.81 Withbehavioral disturbance 294.10 F02.80 Without behavioral disturbance331.9 G31.9 Major neurocognitive disorder with Lewy bodies, PossibleMajor neurocognitive disorder with Lewy bodies, Probable (code first331.82 [G31.83] Lewy body disease) 294.11 F02.81 With behavioraldisturbance 294.10 F02.80 Without behavioral disturbance Majorneurocognitive disorder due to multiple etiologies 294.11 F02.81 Withbehavioral disturbance 294.10 F02.80 Without behavioral disturbance331.9 G31.9 Major neurocognitive disorder due to Parkinson's disease,Possible Major neurocognitive disorder due to Parkinson's disease,Probable (code first 332.0 [G20] Parkinson's disease 294.11 F02.81 Withbehavioral disturbance 294.10 F02.80 Without behavioral disturbanceMajor neurocognitive disorder due to prion disease (code first 046.79[A81.9] prion disease) 294.11 F02.81 With behavioral disturbance 294.10F02.80 Without behavioral disturbance Major neurocognitive disorder dueto traumatic brain injury (code first 907.0 late effect of intracranialinjury without skull fracture [S06.2X9S diffuse traumatic brain injurywith loss of consciousness of unspecified duration, sequela]) 294.11F02.81 With behavioral disturbance 294.10 F02.80 Without behavioraldisturbance 331.9 G31.9 Major vascular neurocognitive disorder, PossibleMajor vascular neurocognitive disorder, Probable 290.40 F01.51 Withbehavioral disturbance 290.40 F01.50 Without behavioral disturbance302.71 F52.0 Male hypoactive sexual desire disorder V65.2 Z76.5Malingering 333.99 G25.71 Medication-induced acute akathisia 333.72G24.02 Medication-induced acute dystonia 292.81 Medication-induceddelirium (For ICD-10-CM codes, see specific substances) 333.1 G25.1Medication-induced postural tremor 331.83 G31.84 Mild frontotemporalneurocognitive disorder 331.83 G31.84 Mild neurocognitive disorder dueto Alzheimer's disease 331.83 G31.84 Mild neurocognitive disorder due toanother medical condition 331.83 G31.84 Mild neurocognitive disorder dueto HIV infection 331.83 G31.84 Mild neurocognitive disorder due toHuntington's disease 331.83 G31.84 Mild neurocognitive disorder due tomultiple etiologies 331.83 G31.84 Mild neurocognitive disorder due toParkinson's disease 331.83 G31.84 Mild neurocognitive disorder due toprion disease 331.83 G31.84 Mild neurocognitive disorder due totraumatic brain injury 331.83 G31.84 Mild neurocognitive disorder withLewy bodies 331.83 G31.84 Mild vascular neurocognitive disorder 301.81F60.81 Narcissistic personality disorder Narcolepsy 347.00 G47.419Autosomal dominant cerebellar ataxia, deafness, and narcolepsy 347.00G47.419 Autosomal dominant narcolepsy, obesity, and type 2 diabetes347.10 G47.429 Narcolepsy secondary to another medical condition 347.01G47.411 Narcolepsy with cataplexy but without hypocretin deficiency347.00 G47.419 Narcolepsy without cataplexy but with hypocretindeficiency 332.1 G21.11 Neuroleptic-induced parkinsonism 333.92 G21.0Neuroleptic malignant syndrome 307.47 F51.5 Nightmare disorder V15.81Z91.19 Nonadherence to medical treatment Non-rapid eye movement sleeparousal disorders 307.46 F51.4 Sleep, terror type 307.46 F51.3Sleepwalking type 300.3 F42 Obsessive-compulsive disorder 301.4 F60.5Obsessive-compulsive personality disorder 294.8 F06.8Obsessive-compulsive and related disorder due to another medicalcondition 327.23 G47.3 Obstructive sleep apnea hypopnea 292.89Opioid-induced anxiety disorder F11.188 With mild use disorder F11.288With moderate or severe use disorder F11.988 Without use disorderF11.921 Opioid-induced delirium 292.84 Opioid-induced depressivedisorder F11.14 With mild use disorder F11.24 With moderate or severeuse disorder F11.94 Without use disorder 292.89 Opioid-induced sexualdysfunction F11.181 With mild use disorder F11.281 With moderate orsevere use disorder F11.981 Without use disorder 292.85 Opioid-inducedsleep disorder F11.182 With mild use disorder F11.282 With moderate orsevere use disorder F11.982 Without use disorder 292.89 Opioidintoxication Opioid intoxication, With perceptual disturbances F11.122With mild use disorder F11.222 With moderate or severe use disorderF11.922 Without use disorder Opioid intoxication, Without perceptualdisturbances F11.129 With mild use disorder F11.229 With moderate orsevere use disorder F11.929 Without use disorder 292.81 Opioidintoxication delirium F11.121 With mild use disorder F11.221 Withmoderate or severe use disorder F11.921 Without use disorder Opioid usedisorder 305.50 F11.10 Mild 304.00 F11.20 Moderate 304.00 F11.20 Severe292.0 F11.23 Opioid withdrawal 292.0 F11.23 Opioid withdrawal delirium313.81 F91.3 Oppositional defiant disorder Other adverse effect ofmedication 995.20 T50.905A Initial encounter 995.20 T50.905S Sequelae995 20 T50.905D Subsequent encounter Other circumstances related toadult abuse by nonspouse or nonpartner V62.83 Z69.82 Encounter formental health services for perpetrator of nonspousal adult abuse V65.49Z69.81 Encounter for mental health services for victim of nonspousaladult abuse Other circumstances related to child neglect V62.83 Z69.021Encounter for mental health services for perpetrator of nonparentalchild neglect V61.22 Z69.011 Encounter for mental health services forperpetrator of parental child neglect V61.21 Z69.010 Encounter formental health services for victim of child neglect by parent V61.21Z69.020 Encounter for mental health services for victim of nonparentalchild neglect V15.42 Z62.812 Personal history (past history) of neglectin childhood Other circumstances related to child physical abuse V62.83Z69.021 Encounter for mental health services for perpetrator ofnonparental child abuse V61.22 Z69.011 Encounter for mental healthservices for perpetrator of parental child abuse V61.21 Z69.010Encounter for mental health services for victim of child abuse by parentV61.21 Z69.020 Encounter for mental health services for victim ofnonparental child abuse V15.41 Z62.810 Personal history (past history)of physical abuse in childhood Other circumstances related to childpsychological abuse V62.83 Z69.021 Encounter for mental health servicesfor perpetrator of nonparental child psychological abuse V61.22 Z69.011Encounter for mental health services for perpetrator of parental childpsychological abuse V61.21 Z69.010 Encounter for mental health servicesfor victim of child psychological abuse by parent V61.21 Z69.020Encounter for mental health services for victim of nonparental childpsychological abuse V15.42 Z62.811 Personal history (past history) ofpsychological abuse in childhood Other circumstances related to childsexual abuse V62.83 Z69.021 Encounter for mental health services forperpetrator of nonparental child sexual abuse V61.22 Z69.011 Encounterfor mental health services for perpetrator of parental child sexualabuse V61.21 Z69.010 Encounter for mental health services for victim ofchild sexual abuse by parent V61.21 Z69.020 Encounter for mental healthservices for victim of nonparental child sexual abuse V15.41 Z62.810Personal history (past history) of sexual abuse in childhood Othercircumstances related to spouse or partner abuse, Psychological V61.12Z69.12 Encounter for mental health services for perpetrator of spouse orpartner psychological abuse V61.11 Z69.11 Encounter for mental healthservices for victim of spouse or partner psychological abuse V15.42Z91.411 Personal history (past history) of spouse or partnerpsychological abuse Other circumstances related to spouse or partnerneglect V61.12 Z69.12 Encounter for mental health services forperpetrator of spouse or partner neglect V61.11 Z69.11 Encounter formental health services for victim of spouse or partner neglect V15.42Z91.412 Personal history (past history) of spouse or partner neglectOther circumstances related to spouse or partner violence, PhysicalV61.12 Z69.12 Encounter for mental health services for perpetrator ofspouse or partner violence, Physical V61.11 Z69.11 Encounter for mentalhealth services for victim of spouse or partner violence, PhysicalV15.41 Z91.410 Personal history (past history) of spouse or partnerviolence, Physical Other circumstances related to spouse or partnerviolence, Sexual V61.12 Z69.12 Encounter for mental health services forperpetrator of spouse or partner violence, Sexual V61.11 Z69.81Encounter for mental health services for victim of spouse or partnerviolence, Sexual V15.41 Z91.410 Personal history (past history) ofspouse or partner violence, Sexual V65.40 Z71.9 Other counseling orconsultation 292.89 Other hallucinogen-induced anxiety disorder F16.180With mild use disorder F16.280 With moderate or severe use disorderF16.980 Without use disorder 292.84 Other hallucinogen-induced bipolarand related disorder F16.14 With mild use disorder F16.24 With moderateor severe use disorder F16.94 Without use disorder 292.84 Otherhallucinogen-induced depressive disorder F16.14 With mild use disorderF16.24 With moderate or severe use disorder F16.94 Without use disorder292.9 Other hallucinogen-induced psychotic disorder F16.159 With milduse disorder F16.259 With moderate or severe use disorder F16.959Without use disorder 292.89 Other hallucinogen intoxication F16.129 Withmild use disorder F16.229 With moderate or severe use disorder F16.929Without use disorder 292.81 Other hallucinogen intoxication deliriumF16.121 With mild use disorder F16.221 With moderate or severe usedisorder F16.921 Without use disorder Other hallucinogen use disorder305.30 F16.10 Mild 304.50 F16.20 Moderate 304.50 F16.20 Severe 333.99G25.79 Other medication-induced movement disorder 332.1 G21.19 Othermedication-induced parkinsonism V15.49 Z91.49 Other personal history ofpsychological trauma V15.89 Z91.89 Other personal risk factors V62.29Z56.9 Other problem related to employment V62.89 Z65.8 Other problemrelated to psychosocial circumstances 300.09 F41.8 Other specifiedanxiety disorder 314.01 F90.8 Other specifiedattention-deficit/hyperactivity disorder 296.89 F31.89 Other specifiedbipolar and related disorder 780.09 R41.0 Other specified delirium 311F32.8 Other specified depressive disorder 312.89 F91.8 Other specifieddisruptive, impulse-control, and conduct disorder 300.15 F44.89 Otherspecified dissociative disorder Other specified elimination disorder787.60 R15.9 With fecal symptoms 788.39 N39.498 With urinary symptoms307.59 F50.8 Other specified feeding or eating disorder 302.6 F64.8Other specified gender dysphoria 780.54 G47.19 Other specifiedhypersomnolence disorder 780.52 G47.09 Other specified insomnia disorder300.9 F99 Other specified mental disorder 294.8 F06.8 Other specifiedmental disorder due to another medical condition 315.8 F88 Otherspecified neurodevelopmental disorder 300.3 F42 Other specifiedobsessive-compulsive and related disorder 302.89 F65.89 Other specifiedparaphilic disorder 301.89 F60.89 Other specified personality disorder298.8 F28 Other specified schizophrenia spectrum and other psychoticdisorder 302.79 F52.8 Other specified sexual dysfunction 780.59 G47.8Other specified sleep-wake disorder 300.89 F45.8 Other specified somaticsymptom and related disorder 307.20 F95.8 Other specified tic disorder309.89 F43.8 Other specified trauma- and stressor-related disorder292.89 Other (or unknown) substance-induced anxiety disorder F19.180With mild use disorder F19.280 With moderate or severe use disorderF19.980 Without use disorder 292.84 Other (or unknown) substance-inducedbipolar and related disorder F19.14 With mild use disorder F19.24 Withmoderate or severe use disorder F19.94 Without use disorder F19.921Other (or unknown) substance-induced delirium 292.84 Other (or unknown)substance-induced depressive disorder F19.14 With mild use disorderF19.24 With moderate or severe use disorder F19.94 Without use disorder292.82 Other (or unknown) substance-induced major neurocognitivedisorder F19.17 With mild use disorder F19.27 With moderate or severeuse disorder F19.97 Without use disorder 292.89 Other (or unknown)substance-induced mild neurocognitive disorder F19.188 With mild usedisorder F19.288 With moderate or severe use disorder F19.988 Withoutuse disorder 292.89 Other (or unknown) substance-inducedobsessive-compulsive and related disorder F19.188 With mild use disorderF19.288 With moderate or severe use disorder F19.988 Without usedisorder 292.9 Other (or unknown) substance-induced psychotic disorderF19.159 With mild use disorder F19.259 With moderate or severe usedisorder F19.959 Without use disorder 292.89 Other (or unknown)substance-induced sexual dysfunction F19.181 With mild use disorderF19.281 With moderate or severe use disorder F19.981 Without usedisorder 292.85 Other (or unknown) substance-induced sleep disorderF19.182 With mild use disorder F19.282 With moderate or severe usedisorder F19.982 Without use disorder 292.89 Other (or unknown)substance intoxication F19.129 With mild use disorder F19.229 Withmoderate or severe use disorder F19.929 Without use disorder 292.81Other (or unknown) substance intoxication delirium F19.121 With mild usedisorder F19.221 With moderate or severe use disorder F19.921 Withoutuse disorder Other (or unknown) substance use disorder 305.90 F19.10Mild 304.90 F19.20 Moderate 304.90 F19.20 Severe 292.0 F19.239 Other (orunknown) substance withdrawal 292.0 F19.231 Other (or unknown) substancewithdrawal delirium Other or unspecified stimulant use disorder 305.70F15.10 Mild 304.40 F15.20 Moderate 304.40 F15.20 Severe 278.00 E66.9Overweight or obesity Panic attack specifier 300.01 F41.0 Panic disorder301.0 F60.0 Paranoid personality disorder V61.20 Z62.820 Parent-childrelational problem 302.2 F65.4 Pedophilic disorder 307.22 F95.1Persistent (chronic) motor or vocal tic disorder 300.4 F34.1 Persistentdepressive disorder (dysthymia) V62.22 Z91.82 Personal history ofmilitary deployment V15.59 Z91.5 Personal history of self-harm 310.1F07.0 Personality change due to another medical condition V62.89 Z60.0Phase of life problem 292.89 Phencyclidine-induced anxiety disorderF16.180 With mild use disorder F16.280 With moderate or severe usedisorder F16.980 Without use disorder 292.84 Phencyclidine-inducedbipolar and related disorder F16.14 With mild use disorder F16.24 Withmoderate or severe use disorder F16.94 Without use disorder 292.84Phencyclidine-induced depressive disorder F16.14 With mild use disorderF16.24 With moderate or severe use disorder F16.94 Without use disorder292.9 Phencyclidine-induced psychotic disorder F16.159 With mild usedisorder F16.259 With moderate or severe use disorder F16.959 Withoutuse disorder 292.89 Phencyclidine intoxication F16.129 With mild usedisorder F16.229 With moderate or severe use disorder F16.929 Withoutuse disorder 292.81 Phencyclidine intoxication delirium F16.121 Withmild use disorder F16.221 With moderate or severe use disorder F16.921Without use disorder Phencyclidine use disorder 305.90 F16.10 Mild304.60 F16.20 Moderate 304.60 F16.20 Severe 307.52 Pica F50.8 In adultsF98.3 In children 309.81 F43.10 Posttraumatic stress disorder 302.75F52.4 Premature (early) ejaculation 625.4 N94.3 Premenstrual dysphoricdisorder V62.21 Z56.82 Problem related to current military deploymentstatus V69.9 Z72.9 Problem related to lifestyle V60.3 Z60.2 Problemrelated to living alone V60.6 Z59.3 Problem related to living in aresidential institution V61.5 Z64.1 Problems related to multiparityV62.5 Z65.3 Problems related to other legal circumstances V62.5 Z65.2Problems related to release from prison V61.7 Z64.0 Problems related tounwanted pregnancy 307.21 F95.0 Provisional tic disorder 316 F54Psychological factors affecting other medical conditions Psychoticdisorder due to another medical condition 293.81 F06.2 With delusions293.82 F06.0 With hallucinations 312.33 F63.1 Pyromania 327.42 G47.52Rapid eye movement sleep behavior disorder 313.89 F94.1 Reactiveattachment disorder V61.10 Z63.0 Relationship distress with spouse orintimate partner V62.89 Z65.8 Religious or spritual problem 333.94G25.81 Restless legs syndrome 307.53 F98.21 Rumination disorderSchizoaffective disorder 295.70 F25.0 Bipolar type 295.70 F25.1Depressive type 301.20 F60.1 Schizoid personality disorder 295.90 F20.9Schizophrenia 295.40 F20.81 Schizophreniform disorder 301.22 F21Schizotypal personality disorder 292.89 Sedative-, hypnotic-, oranxiolytic-induced anxiety disorder F13.180 With mild use disorderF13.280 With moderate or severe use disorder F13.980 Without usedisorder 292.84 Sedative-, hypnotic-, or anxiolytic-induced bipolar andrelated disorder F13.14 With mild use disorder F13.24 With moderate orsevere use disorder F13.94 Without use disorder F13.921 Sedative-,hypnotic-, or anxiolytic-induced delirium 292.84 Sedative-, hypnotic-,or anxiolytic-induced depressive disorder F13.14 With mild use disorderF13.24 With moderate or severe use disorder F13.94 Without use disorder292.82 Sedative-, hypnotic-, or anxiolytic-induced major neurocognitivedisorder F13.27 With moderate or severe use disorder F13.97 Without usedisorder 292.89 Sedative-, hypnotic-, or anxiolytic-induced mildneuroconitive disorder F13.288 With moderate or severe use disorderF13.988 Without use disorder 292.9 Sedative-, hypnotic-, oranxiolytic-induced psychotic disorder F13.159 With mild use disorderF13.259 With moderate or severe use disorder F13.959 Without usedisorder 292.89 Sedative-, hypnotic-, or anxiolytic-induced sexualdysfunction F13.181 With mild use disorder F13.281 With moderate orsevere use disorder F13.981 Without use disorder 292.85 Sedative-,hypnotic-, or anxiolytic-induced sleep disorder F13.182 With mild usedisorder F13.282 With moderate or severe use disorder F13.982 Withoutuse disorder 292.89 Sedative, hypnotic, or anxiolytic intoxicationF13.129 With mild use disorder F13.229 With moderate or severe usedisorder F13.929 Without use disorder 292.81 Sedative, hypnotic, oranxiolytic intoxication delirium F13.121 With mild use disorder F13.221With moderate or severe use disorder F13.921 Without use disorderSedative, hypnotic, or anxiolytic use disorder 305.40 F13.10 Mild 304.10F13.20 Moderate 304.10 F13.20 Severe 292.0 Sedative, hypnotic, oranxiolytic withdrawal F13.232 With perceptual disturbances F13.239Without perceptual disturbances 292.0 F13.231 Sedative, hypnotic, oranxiolytic withdrawal delirium 313.23 F94.0 Selective mutism 309.21F93.0 Separation anxiety disorder V65.49 Z70.9 Sex counseling 302.83F65.51 Sexual masochism disorder 302.84 F65.52 Sexual sadism disorderV61.8 Z62.891 Sibling relational problem Sleep-related hypoventilation327.26 G47.36 Comorbid sleep-related hypoventilation 327.25 G47.35Congenital central alveolar hypoventilation 327.24 G47.34 Idiopathichypoventilation 300.23 F40.10 Social anxiety, disorder (social phobia)V62.4 Z60.4 Social exclusion or rejection 315.39 F80.89 Social(pragmatic) communication disorder 300.82 F45.1 Somatic symptom disorderSpecific learning disorder 315.1 F81.2 With impairment in mathematics315.00 F81.0 With impairment in reading 315.2 F81.81 With impairment inwritten expression Specific phobia 300.29 F40.218 Animal 300.29Blood-injection-injury F40.230 Fear of blood F40.231 Fear of iniectionsand transfusions F40.233 Fear of injury F40.232 Fear of other medicalcare 300.29 F40.228 Natural environment 300.29 F40.298 Other 300.29F40.248 Situational 315.39 F80.0 Speech sound disorder Spouse or partnerabuse, Psychological, Confirmed 995.82 T74.31XA Initial encounter 995.82T74.31XD Subsequent encounter Spouse or partner abuse, Psychological,Suspected 995.82 T76.31XA Initial encounter 995.82 T76.31XD Subsequentencounter Spouse or partner neglect, Confirmed 995.85 T74.01XA Initialencounter 995.85 T74.01XD Subsequent encounter Spouse or partnerneglect, Suspected 995.85 T76.01XA Initial encounter 995.85 T76.01XDSubsequent encounter Spouse or partner violence, Physical, Confirmed995.81 T74.11XA Initial encounter 995.81 T74.11XD Subsequent encounterSpouse or partner violence, Physical, Suspected 995.81 T76.11XA Initialencounter 995.81 T76.11XD Subsequent encounter Spouse or partnerviolence, Sexual, Confirmed 995.83 T74.21XA Initial encounter 995.83T74.21XD Subsequent encounter Spouse or partner violence, Sexual,Suspected 995.83 T76.21XA Initial encounter 995.83 T76.21XD Subsequentencounter 307.3 F98.4 Stereotypic movement disorder Stimulantintoxication (see amphetamine or cocaine intoxication for specificcodes) Stimulant use disorder (see amphetamine or cocaine use disorderfor specific codes) Stimulant withdrawal (see amphetamine or cocainewithdrawal for specific codes) Substance intoxication delirium (seespecific substances for codes) Substance withdrawal delirium (seespecific substances for codes) Substance/medication-induced anxietydisorder (see specific substances for codes)Substance/medication-induced bipolar and related disorder (see specificsubstances for codes) Substance/medication-induced depressive disorder(see specific substances for codes) Substance/medication-induced majoror mild neurocognitive disorder (see specific substances for codes)Substance/medication-induced obsessive-compulsive and related disorder(see specific substances for codes) Substance/medication-inducedpsychotic disorder (see specific substances for codes)Substance/medication-induced sexual dysfunction (see specific substancesfor codes) Substance/medication-induced sleep disorder (see specificsubstances for codes) 333.99 G25.71 Tardive akathisia 333.85 G24.01Tardive dyskinesia 333.72 G24.09 Tardive dystonia V62.4 Z60.5 Target of(perceived) adverse discrimination or persecution 292.85 Tobacco-inducedsleep disorder F17.208 With moderate or severe use disorder Tobacco usedisorder 305.1 Z72.0 Mild 305.1 F17.200 Moderate 305.1 F17.200 Severe292.0 F17.203 Tobacco withdrawal 307.23 F95.2 Tourette's disorder 302.3F65.1 Transvestic disorder 312.39 F63.3 Trichotillomania (hair-pullingdisorder) V63.9 Z75.3 Unavailability or inaccessibility of health carefacilities V63.8 Z75.4 Unavailability or inaccessibility of otherhelping agencies V62.82 Z63.4 Uncomplicated bereavement 291.9 F10.99Unspecified alcohol-related disorder 300.00 F41.9 Unspecified anxietydisorder 314.01 F90.9 Unspecified attention-deficit/hyperactivitydisorder 296.80 F31.9 Unspecified bipolar and related disorder 292.9F15.99 Unspecified caffeine-related disorder 292.9 F12.99 Unspecifiedcannabis-related disorder 293.89 F06.1 Unspecified catatonia (code first781.99 [R29.818] other symptoms involving nervous and musculoskeletalsystems) 307.09 F80.9 Unspecified communiction disorder 780.09 R41.0Unspecified delirium 311 F32.9 Unspecified depressive discirder 312.9F91.9 Unspecified disruptive, impulse-control, and conduct disorder300.15 F44.9 Unspecified dissociative disorder Unspecified eliminationdisorder 787.60 R15.9 With fecal symptoms 788.30 R32 With urinarysymptoms 307.50 F50.9 Unspecified feeding or eating disorder 302.6 F64.9Unspecified gender dysphoria 292.9 F16.99 Unspecifiedhallucinogen-related disorder V60.9 Z59.9 Unspecified housing oreconomic problem 780.54 G47.10 Unspecified hypersomnolence disorder292.9 F18.99 Unspecified inhalant-related disorder 780.52 G47.00Unspecified insomnia disorder 319 F79 Unspecified intellectualdisability (intellectual developmental disorder) 300.9 F99 Unspecifiedmental disorder 294.9 F09 Unspecified mental due to another medicalcondition 799.59 R41.9 Unspecified neurocognitive disorder 315.9 F89Unspecified neurodevelopmental disorder 300.3 F42 Unspecifiedobsessive-compulsive and related disorder 292.9 F11.99 Unspecifiedopioid-related disorder 292.9 F19.99 Unspecified other (or unknown)substance- related disorder 302.9 F65.9 Unspecified paraphilic disorder301.9 F60.9 Unspecified personality disorder 292.9 F16.99 Unspecifiedphencyclidine-related disorder V62.9 Z60.9 Unspecified problem relatedto social environment V62.9 Z65.9 Unspecified problem related tounspecified psychosocial circumstances 298.9 F29 Unspecifiedschizophrenia spectrum and other psychotic disorder 292.9 F13.99Unspecified sedative-, hypnotic-, or anxiolytic-related disorder 302.70F52.9 Unspecified sexual dysfunction 780.59 G47.9 Unspecified sleep-wakedisorder 300.82 F45.9 Unspecified somatic symptom and related disorder292.9 Unspecified stimulant-related disorder F15.99 Unspecifiedamphetamine or other stimulant- related disorder F14.99 Unspecifiedcocaine-related disorder 307.20 F95.9 Unspecified tic disorder 292.9F17.209 Unspecified tobacco-related disorder 309.9 F43.9 Unspecifiedtrauma- and stressor-related disorder V61.8 Z62.29 Upbringing away fromparents V62.89 Z65.4 Victim of crime V62.89 Z65.4 Victim of terrorism ortorture 302.82 F65.3 Voyeuristic disorder V40.31 Z91.83 Wanderingassociated with a mental disorder

1. A sublingual formulation comprising an effective amount of riluzoleor a pharmaceutically acceptable salt, solvate, anomer, enantiomer,hydrate or prodrug thereof.
 2. The sublingual formulation of claim 1wherein the riluzole comprises a riluzole prodrug.
 3. A method ofproviding a therapeutic benefit to a subject by administering to thesubject an effective amount of a sublingual riluzole or apharmaceutically acceptable salt, solvate, anomer, enantiomer, hydrateor prodrug thereof.
 4. The method of claim 3, wherein the subject ishuman.
 5. A method of claim 4 wherein the therapeutic benefit isprovided to the subject to treat a neuropsychiatric disorder or symptom.6. The method of claim 5 wherein the neuropsychiatric disorder isanxiety disorders, mood disorders, neurodegenerative disorders, paindisorders, ALS, cognitive disorders, Huntington's disease, Parkinson'sdisease, supranuclear palsy, frontotemporal dementia, frontotemporallobar degeneration, schizophrenia, delirium, Alzheimer's disease, mildcognitive impairment, mild cognitive impairment due to Alzheimer'sdisease, ataxia, hereditary ataxia, depression, mania, attention deficitdisorders, drug addiction, dementia, agitation, apathy, anxiety,psychoses, post-traumatic stress disorders, irritability, anddisinhibition, learning disorders, memory loss, mental retardation, RettSyndrome, tinnitus, personality disorders, bipolar disorders,obsessive-compulsive disorders, eating disorders, conduct disorders inDSM-5 and or combinations thereof.
 7. The method of claim 5, wherein theneuropsychiatric symptom is anxiety, depression, stress, fatigue,feelings of panic, fear, uneasiness, problems in sleeping, cold orsweaty hands and/or feet, mood liability, mania, impaired concentrationor attention, cognitive problems, obsessions, compulsions, repetitivebehaviors, aggression, social phobias or impairments, stage fright,shortness of breath, heart palpitations, an inability to be still andcalm, dry mouth, numbness or tingling in the hands or feet, nausea,muscle tension, dizziness apathy, elation, disinhibition, irritability,wandering, irritable bowel, belly pain, belly discomfort, diarrhea,change in bowel habits, abdominal bloating, abdominal gas, abdominalbloating, constipation or combinations thereof.
 8. The method of claim 3wherein the effective amount of riluzole for the sublingual formulationto achieve a therapeutic dose is less than that of orally administeredriluzole.
 9. The method of claim 3, wherein an effective dose of thesublingual formulation of the riluzole is about 1 to 95% of that of theorally administered riluzole.
 10. The method of claim 1, wherein thesublingual formulation of riluzole produces a rapid therapeutic onset ofaction within minutes.
 11. The method of claim 3, wherein the sublingualformulation of riluzole is associated with minimal or no oral numbness,or said oral numbness dissipates in less than 30 minutes.
 12. The methodof claim 3 wherein the sublingual formulation delivers an exposure (AUC)similar to a higher orally administered dose of riluzole.
 13. The methodof claim 3 wherein the liver function abnormalities side effects ofriluzole are attenuated relative to those which are associated with theorally administered riluzole.
 14. The method of claim 3 wherein thesublingual formulation is dosed at or below an amount selected fromabout 70 mg/day, about 50 mg/day, about 35 mg/day, about 17.5 mg/day,about 10 mg/day, about 5 mg/day or about 1 mg/day.
 15. The method ofclaim 3 wherein the sublingual formulation comprises a riluzole prodrug.16. A method of relieving or reducing oral pain of a subject in atreatment area of oral pain is throughout an oral cavity including theupper surface of the tongue, lips, buccal area, back of throat, entireoral cavity or combinations thereof by administering an effective amountof the sublingual formulation of claim 3 in the oral cavity.
 17. Themethod of claim 15, the oral pain for treatment is caused by infection,inflammation, burn, cut, toothache, sore gums, canker sores, braces,minor dental procedures, denture irritation, oral surgery, neurologicdisorders, disorders of the mucosa, oral ulcers, chemotherapy agents orcombinations thereof.
 18. The sublingual formulation of claim 3 whereinthe sublingual formulation has a greater C_(max) than the same dose oforally administered riluzole.
 19. The sublingual formulation of claim 3,wherein the sublingual formulation has an earlier or lesser T_(max) thanthe same dose of orally administered riluzole.
 20. The sublingualformulation of claim 3, wherein the sublingual formulation has a greaterAUC per milligram of the riluzole than the same dose of orallyadministered riluzole.
 21. A sublingual or sustained release formulationcomprising an effective amount of riluzole or a pharmaceuticallyacceptable salts, solvate, anomers, enantiomers, hydrate or prodrugsthereof to treat irritable bowel syndrome.